Oleanolic Acid and Ursolic Acid Alleviate Obesity-Induced Skeletal Muscle Atrophy via Activation of the IRS/PI3K/AKT/mTOR Signaling Pathway and Attenuation of Oxidative Stress

Oleanolic acid (OA) and ursolic acid (UA) are dietary pentacyclic triterpenoids with anti-inflammatory and insulin-sensitizing properties, but their comparative effects on obesity-related skeletal muscle atrophy remain unclear. In this study, high-fat diet-fed C57BL/6J mice and palmitic acid-treated C2C12 cells were used to evaluate their efficacy and mechanisms. OA and UA improved glucose homeostasis, attenuated muscle atrophy, and alleviated dyslipidemia and inflammation. Mechanistically, both compounds activated IRS/AKT/mTOR signaling, suppressed GSK-3β/FOXO1-mediated catabolism, alleviated endoplasmic reticulum stress, and regulated autophagy balance. They also enhanced mitochondrial function and biogenesis. Transcriptomic and CMap analyses suggested PSMB1 as a potential target. In vitro, OA and UA improved mitochondrial respiration, ATP production, and glucose uptake. Overall, OA and UA effectively mitigate HFD-induced muscle atrophy through coordinated regulation of insulin signaling, proteostasis, and mitochondrial function.